Management of two circulations in a COVID‐19 patient with secondary superinfection

Abstract Optimal oxygenation in the intensive care unit requires adequate pulmonary gas exchange, oxygen‐carrying capacity in the form of hemoglobin, sufficient delivery of oxygenated hemoglobin to the tissue, and an appropriate tissue oxygen demand. In this Case Study in Physiology, we describe a patient with COVID‐19 whose pulmonary gas exchange and oxygen delivery were severely compromised by COVID‐19 pneumonia requiring extracorporeal membrane oxygenation (ECMO) support. His clinical course was complicated by a secondary superinfection with staphylococcus aureus and sepsis. This case study is provided with two goals in mind (1) We outline how basic physiology was used to address life‐threatening consequences of a novel infection—COVID‐19. (2) We describe a strategy of whole‐body cooling to lower the cardiac output and oxygen consumption, use of the shunt equation to optimize flow to the ECMO circuit, and transfusion to improve oxygen‐carrying capacity when ECMO alone failed to provide sufficient oxygenation.

opacification of both lung fields (Figure 1). Respiratory and blood cultures grew Methicillin-sensitive Staphylococcus aureus (MSSA). A transthoracic echocardiogram (TTE) demonstrated an ejection fraction of 73% with normal left ventricular systolic function and no valvular pathology. Tricuspid annular plane systolic excursion was 27 mm, indicating normal right ventricular function. An arterial blood gas revealed pH 7.51, PaCO 2 45 mmHg, and PaO 2 39 mmHg. His ECMO settings were maximized with a circuit blood flow of 6 L/ min and sweep gas flow of 15 L/min. There was no significant ECMO-circuit recirculation, and central venous saturation (SvO 2 ) was 45%.
Despite maximal support, SaO 2 was consistently between 73% and 82%, regardless of ventilator FIO 2 of 0.3 or 1.0, indicating that all gas exchange was occurring within the ECMO circuit and there was negligible pulmonary gas exchange (Table 1 and   Abbreviations: BP, blood pressure; CaO 2 , Oxygen content of arterial blood-calculation based on Equation (6) in main text; CecO 2 , "endcapillary" content of oxygen = post-ECMO-oxygenator content of oxygen; CvO 2 , oxygen content of venous blood; et, endtidal; FiO 2 , fraction of oxygen in inspired air; Hgb, hemoglobin; HR, heart rate in beats per minute (bpm); PaCO 2 , partial pressure of CO 2 in arterial blood; PaO 2 , partial pressure of O 2 in arterial blood; PecO 2 , "endcapillary" partial pressure of oxygen = post-ECMO-oxygenator partial pressure of oxygen; SaO 2 , saturation of arterial blood with oxygen; SvO 2 , saturation of central venous blood with oxygen; Temp, temperature in °C; TV, Tidal Volume; Δ P, delta pressure over ECMO membrane oxygenator. sedated and paralyzed on pressure control ventilation with pressure control of +10 cm H 2 O above a PEEP of 10 cm H 2 O with a resulting tidal volume of 30-40 mL (respiratory system compliance of 3-4 mL/cm H 2 O). The patient had a lactate of 2.3 mmoL/L (normal 0.5-2.2 mmoL/L) and hemoglobin of 7.5 g/dL in the absence of active bleeding. Our efforts at improving pulmonary gas exchange with recruitment maneuvers, bronchoscopies to clear airways, and attempts to ventilate in the prone position were not successful. Complete pulmonary failure persisted. Considering our patient's worsening, critical hypoxemia (SpO 2 73%-82%), we proceeded to cool the patient by 1°C to reduce oxygen consumption, increase SvO 2 , and lower systemic cardiac output. These interventions yielded immediate effect (SpO 2 86%-90%). In addition, we made efforts to increase oxygen-carrying capacity and ensure adequate intravascular volume, through judicious transfusion of packed red blood cells (PRBCs). Although these efforts improved oxygenation, the patient ultimately succumbed to acute respiratory distress syndrome related to COVID-19 with MSSA superinfection.

| DISCUSSION
The strategies we used were intended to optimize oxygenation in a patient with severely limited pulmonary gas exchange. These include (A) capturing a greater fraction of the native cardiac output to route it through the VV-ECMO circuit, (B) increasing SvO 2 by lowering oxygen consumption, (C) increasing oxygen-carrying capacity of the blood, and (D) improving pulmonary gas exchange.

| How can the fraction of cardiac output routed through the VV-ECMO circuit be determined and increased?
In our patient, oxygenation occurred entirely within the VV-ECMO circuit. Thus, SaO 2 depended on the fraction of systemic cardiac output reaching the VV-ECMO circuit. When the VV-ECMO blood flow is set and known, it is clinically important to estimate the systemic cardiac output in this setting to know the maximal improvement in oxygenation that can be provided by the circuit.
When pulmonary gas exchange is negligible and oxygenation is provided entirely by the VV-ECMO circuit, the a two compartment model where CecO 2 is the oxygen content in maximally saturated post-ECMO blood, CaO 2 is the oxygen content of arterial blood and CvO 2 is venous oxygen content. Ignoring dissolved oxygen, this can be simplified by calculating the shunt fraction based on oxygen saturations (Walley, 2011). As the saturation of post-ECMO blood is 100%, the shunt equation simplifies to In our patient with a SaO 2 of 74% and SvO 2 of 45%, this equation predicts a shunt fraction of 47% (Table 2a and Figure 3a). Recall that the shunt fraction, in this case, represents the portion of the cardiac output that does not travel through the VV-ECMO circuit. To determine the total cardiac output, we calculate Based on a VV-ECMO blood flow [Q T − Q S ] of 6 L/ min and a shunt fraction [Q S /Q T ] of 47%, we estimate the total cardiac output to be is 11.3 L/min ( Figure 3a and Table 2a). This is consistent with hyperdynamic cardiac output seen in sepsis.
We can use this shunt estimate to predict the maximum ability to raise PaO 2 . Figure 4 shows an iso-shunt diagram, which illustrates the relationship between PaO 2 and FiO 2 in the presence of a shunt (Petersson & Glenny, 2014). In our case of complete pulmonary failure on VV-ECMO support, the FiO 2 is the membrane oxygenator FiO 2 . The iso-shunt lines correspond to different shunt fractions [Q S /Q T ]. With increasing Q S /Q T , the effect of an increase in FiO 2 is a progressively smaller increase in PaO 2 . When the Q S /Q T reaches 50%, there is no significant increase in PaO 2 , even at a FiO 2 of 1 ( Figure 4). Thus, in our patient with a Q s /Q T of 47% (Table 2a and Figure 3a) the best solution is to decrease Q s /Q T by increasing the fraction of flow of systemic cardiac output through the VV-ECMO circuit.
The shunt equation presents a valid approach to estimate systemic cardiac output based on the following observations: (A) There was no change in SaO 2 or PaO 2 in our patient when the ventilator FIO 2 was titrated from 0.3 to 1 and endtidal CO 2 was undetectable (Table 1). Our patient's complete pulmonary failure remained unchanged with ongoing "white out" on CXR (Figure 1) with a severely reduced respiratory system compliance of 3-4 mL/ cm H 2 O. (B) There was no evidence of ECMO circuit recirculation and (C) a similar systemic cardiac output [Q T ] measurement from transthoracic echo was confirmed on VV-ECMO day#13.
From the transthoracic echo, the left ventricular outflow tract (LVOT) diameter was 2.51 cm and the velocity time integral (VTI) was 20.69 cm/contraction. Based on Table 2) F I G U R E 3 VV-ECMO model. Panel (a) exemplifies the hyperdynamic, septic state with high cardiac output [Q T ] of 11.3 L/ min. In the setting of severe lung injury with complete pulmonary failure, oxygenation is dependent on ECMO blood flow (6 L/min). In this example, 5.3 L/min (47% of the venous return) will shunt [Q S ] through the vena cava without oxygenation. With a shunt fraction [Q S /Q T ] of 47% and a low SvO 2 of 45%, the result is severe hypoxemia with an SaO 2 of only 74%. Panel (b) exemplifies the effect of cooling on cardiac output [Q T ] and SvO 2 . In the setting of severe lung injury with complete pulmonary failure, oxygenation is dependent on ECMO blood flow (6 L/min). After cooling by 1°C on unchanged ECMO settings (compared to Panel a) cardiac output [Q T ] decreased to 8.6 L/min (from 11.3 L/min) and the shunt fraction [Q S /Q T ] decreased to 30% (from 47%). SvO 2 increased to 63% (from 45%) as a result from lower oxygen consumption from cooling. these measurements, the estimate of stroke volume (SV) was 102 mL: With a heart rate (HR) of 89 beats/min, the echo-based estimate of systemic cardiac output was 9.07 L/min (Table 2d): The systemic cardiac output [Q T ] estimate based on VV-ECMO (5.64 L/min ECMO blood flow, SvO 2 46%) and blood gas data (SaO 2 81%) at the time of the echo was 8.7 Lpm and the shunt fraction was 35% (Table 2c). This demonstrates that simple equation bedside estimates of shunt fractions are easy to calculate, and can be calculated frequently, from readily available information.

| How was the fraction of the cardiac output through the VV-ECMO circuit improved?
At maximal capacity, the VV-ECMO circuit can accept and oxygenate 6 L/min of the cardiac output (Nunes et al., 2014). If the cardiac output is reduced, a larger fraction will flow through the ECMO circuit. Our sedated and paralyzed patient was cooled by approximately 1°C from a temperature range of 36.4-36.8°C to 35.3-35.9°C (Table 1). The shunt fraction decreased from 47% precooling to 30% postcooling, and estimated systemic cardiac output decreased from a 11.3 L/min precooling to 8.6 L/min postcooling (Tables 1 and 2b; Figure 3b). Because a greater fraction of the cardiac output flowed through the VV-ECMO circuit, SaO 2 increased from 73%-82% to 87%-89% and SvO 2 increased from 44%-52% range to 56%-68% range.

| How did cooling improve SvO 2 ?
In the setting of a significant shunt, SvO 2 has a substantial impact on SaO 2 . This is illustrated in Figure 5. For example, when the shunt fraction is 50%, and then half of every increase in SvO 2 will be reflected in an increase in SaO 2 . When SvO 2 increases from 50% to 75% (Δ 25%), then SaO 2 increases from 75% to 87.5% (Δ 12.5) (Mishra et al., 2016;Walley, 2011). Another goal of cooling is to reduce oxygen consumption and subsequently increase SvO 2 (Harris et al., 1971;Manthous et al., 1995). Previous work demonstrates that decreased body temperature is associated with decreased oxygen consumption (Harris et al., 1971;Manthous et al., 1995). At physiological temperatures, the relationships between metabolism, oxygen consumption, and hypothermia are particularly pronounced. Rather sharp decreases in oxygen consumption can occur even with small temperature changes. Our sedated and paralyzed patient was cooled by approximately 1°C, and his SvO 2 increased from 45% to 63%, which is best explained by a decrease in oxygen consumption. The O 2 extraction, as reflected in the SaO 2 -SvO 2 difference, was 29% precooling (36.8°C) and 26% postcooling (35.9°C). This 10% reduction in extraction is in line with the empirically derived 10% reduction in metabolism and O 2 consumption per °C reduction in core temperature.

| How was oxygen-carrying capacity improved?
Our patient had a hemoglobin of 7.5 g/dL. Although there was no evidence of active bleeding and our patient did not meet the general threshold for a blood transfusion, we decided to transfuse 1 unit of packed red blood cells. We also raised the hemoglobin transfusion threshold to 8 g/dL. In addition to augmentation of oxygen delivery, the expansion of his intravascular volume via the PRBC administration maintained optimized ECMO blood flows.
Hemoglobin (Hgb) carries nearly all the oxygen in blood, except for a very small component of dissolved oxygen. The total oxygen content in the arterial blood is calculated by the equation: Thus, modulating the concentration of hemoglobin has the greatest ability to alter blood oxygen content. In our patient, considering his marginal oxygen CaO 2 = 1.34 × Hgb × SaO 2 ∕ 100 + 0.003 × PaO 2 F I G U R E 4 Iso-shunt diagram, illustrating the relationship between PaO 2 and FiO 2 in the presence or absence of a shunt. In our patient, FiO 2 is 100% via VV-ECMO. The iso-shunt lines correspond to different percentages of shunt flow in relation to systemic cardiac output (shunt fraction). In the absence of shunt, there is a near linear relationship between PaO 2 and FiO 2 . With increasing shunt fractions, the change in PaO 2 with increasing FiO 2 is much flatter. If the shunt is ≥30% of cardiac output even a FiO 2 of 1.0 results only in a PaO 2 of <100 mmHg.
F I G U R E 5 Impact of SvO 2 on SaO 2 in the setting of a significant shunt. In this example, the shunt fraction is 50%. Then, half of every increase in SvO 2 will be reflected in SaO 2 . As shown in Figure 5, when SvO 2 increases from (a) 50% to (b) 75% (Δ 25), then SaO 2 increases from (a) 75% to (b) 87.5% (Δ 12.5) (Mishra et al., 2016;Walley, 2011). delivery (with an SaO 2 as low as 75%), we decided to transfuse 1 unit of packed red blood cells and temporarily raised the hemoglobin goal to 8 g/dL. This improved oxygen delivery, even when saturation was suboptimal.
2.5 | What attempts were made to improve pulmonary gas exchange?
The goal of ECMO is to allow a pathway to lung recovery by providing adequate oxygenation with ultra-lung protective ventilation to avoid ventilator induced lung injury (Brodie et al., 2019). Furthermore, ECMO support can reduce the need for sedation and facilitate physical therapy. Despite ultra-lung protective ventilation, recruitment maneuvers, and bronchoscopies for airway clearance, our patient continued to have complete pulmonary failure. Prone positioning on ECMO support was not possible, as even small positional changes compromised ECMOcircuit flows with subsequent hypoxemia. Because of sepsis, medical instability, and obesity, ECMO could not provide a bridge to lung transplant. Despite improvements described in this presentation, our patient eventually died from irreversible pulmonary failure due to COVID pneumonia complicated by staphylococcus aureus sepsis (Kurihara et al., 2022).

| SUMMARY
In patients with complete pulmonary failure on VV-ECMO, the "shunt analogy" illustrates the relationship between the two circulations: ECMO circuit blood flow and patient cardiac output.

AUTHOR CONTRIBUTIONS
RS and ME involved in concept and drafting of manuscript. AS, RMR, JH, MB, and GS involved in revision and editing of manuscript.

FUNDING INFORMATION
No funding information provided.

ETHICS STATEMENT
The manuscript is a retrospective case report that does not require ethics committee approval at that institution.